Lower urinary tract (LUT) disorders, that affect the quality of life of millions of people in the world every year, include but are not limited to overactive bladder (OAB), prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence.
OAB is the most common term currently used in clinical medicine to describe a complex of lower urinary tract symptoms with or without incontinence. The symptoms usually include urgency, frequency, nocturia, troublesome or incomplete emptying and occasionally pain. Causes of bladder overactivity include neurological illness or injury, bladder outlet obstruction, urethral weakness, detrusor hyperactivity and impaired contractility in elderly patients, emergence of new voiding reflexes and so-called idiopathic bladder overactivity. Neurogenic overactive bladder occurs as the results of neurological damage due to disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy or spinal cord lesions. By contrast, non-neurogenic OAB can result from non-neurological abnormalities including bladder stones, muscle disease, urinary tract infection or drug side effects. OAB may results from hypersensitivity of sensory neurons of the urinary bladder, arising from various factors including inflammatory conditions, hormonal imbalances, and prostate hypertrophy.
Prostatitis is a term to describe inflammatory conditions of the prostate gland. It is thought that most cases of prostatitis result from bacterial infection, but evidence of infection is not always found. An infected or inflammed prostate can cause painful urination with serious complications. There are four types of prostatitis: acute bacterial prostatitis, chronic bacterial prostatitis, non-bacterial prostatitis and prostadynia, also called chronic pelvic pain syndrome, that is a condition associated with painful symptoms of chronic non-bacterial prostatitis without an inflammation of the prostate.
Interstitial cystitis (IC) is a chronic inflammatory condition of the bladder that causes frequent, urgent and painful urination and pelvic discomfort. Unlike common cystitis (inflammation of the bladder caused by bacterial infection), no infectious agent has been found in IC.
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that is very common in men over 40 years. The prostate grows in two different ways. In one type of growth, cells multiply around the urethra, in the second cells growth into the urethra and the bladder outlet area. This second type of growth typically requires surgery. Common symptoms of BPH include: blood in the urine, feeling that bladder has not emptied completely after the urination, frequent urination, nocturia, urgent need to urinate, incontinence. In severe cases of BPH another symptom is the acute urinary retention.
The function of the LUT is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes involving both the sympathetic and parasympathetic components of the autonomic nervous system and motor pathways.
Urinary incontinence (UI) occurs when the lower urinary tract does not store urine properly and there is involuntary loss of urine. There are 3 types of UI: urge, stress and mixed. Urge UI is considered to be due to an overactive bladder, while stress UI is considered to be due to decreased urethral outlet resistance. Mixed UI contains both components. Symptoms are: urinary frequency, urgency, nocturia, accidental loss of urine. When conscious control of the parasympathetic micturition reflex is compromised, conditions of OAB and/or UI arise, creating serious health and social concerns.
Drugs that suppress the micturition reflex could be useful for treating OAB and UI. One of the target for suppressing the OAB consists in the primary afferent neurons and their peripheral terminals in the bladder. Therapeutic agents that suppress action potential initiation and/or propagation along primary afferent fibers, through modulation of ion channels, would be expected to increase the volume threshold for activation of the micturition reflex and thus reduce bladder overactivity and urgency.
Current treatments for OAB include antimuscarinic drugs, diet modification, programs in bladder training, electrical stimulation and surgery.
Currently, there are no established treatments for prostatitis and prostadynia. Antibiotics, COX-2 inhibitors and α-adrenergic blockers are often prescribed, but their efficacy has not been established.
Treatments for IC that include the administration of antihistamines, sodium pentosanpolysulfate, dimethylsulfoxide, steroids, tricyclic antidepressants and narcotic antagonists have generally been unsuccessful.
Non invasive treatments for BPH include androgen deprivation therapy and the use of 5α-reductase inhibitors and α-adrenergic blockers with minimal efficacy.
Because existing therapies and treatments for LUT disorders are associated with limitations as described above, new therapies and treatments are desirable.
However, despite the large number of available therapeutic agents, their use suffers of limited efficacy and side effects such as dry mouth, dry eyes, dry vagina, palpitations, cardiac rhythm alteration, drowsiness, mental confusion particularly in the elderly and constipation which have proven difficult for individuals to tolerate.
Since sensory afferent neurons, expressing sodium channels, are hypersensitized in bladder disfunctions, it seems reasonable to assume that blocking sodium channels activity may represent a novel strategy for the treatment of lower urinary tract disorders.
The present invention provides rapid and highly effective methods for treating a variety of lower urinary tract disorders by utilizing, in vivo, certain α-aminoamide compounds of the invention in a therapy as an alternative to existing treatments.
WO90/14334, WO94/22808, WO97/05102, WO97/0511 and WO99/35125, the text of which are herein incorporated by reference, disclose substituted benzylaminopropionamide compounds active on the central nervous system and useful as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant and antispastic hypnotic agents (see also Pevarello P. et al. (1998), “Synthesis and anticonvulsant activity of a new class of 2-[(arylalkyl)amino]alkanamide derivatives”, J. Med. Chemistry, 41:579-590). WO99/35125 and WO99/35123 disclose substituted benzylaminopropanamide compounds active on the central nervous system and useful as analgesic agents (see also Veneroni O: et al. (2003) “Anti-allodynic effect of NW-1029, a novel Na+ channel blocker, in experimental animal models of inflammatory and neuropathic pain”, Pain 102(1-2):17-25).